CA1199032A - Derivatives of n-(4-phenylcyclohexy)glycines - Google Patents

Abstract

ABST~CT OF TH~: DISCI.OSURE
N-[4-phenylcyclohexyl)glycines of the formula:
and salts thereof wherein R is H or lower alkyl and R1 is hydrogen or benzoyl are useful as angiotensin I
converting enzyme inhibitors.

Description

- ~ CASE 465 )3,Z

This invention is concerned with derivatives of N-t4-phenylcyclohexyl)glycines which have the formula:

~ (I) R O ~ O
l 11 11 2C C ,, (~I2CO~I

and salts thereof wherein R is H or lower alkyl and R
is hydrogen or benzoyl.

Manifestly the compounds represented by formula (I) exist in geometric isomeric forms as well as diastereoiso-meric forms or racemic mixtures thereof; all being within the scope of this invention.
The compounds are potent inhibitors of the enzyme responsible for converting the decapeptide angiotensin I
to the octapeptide angiotensin II. Angiotensin II is the powerful pressor agent implicated as the causative agent in some forms of hypertension.

Of late, it has been recognized that a substance capable of interrupting the pathway whereby angiotensin II is produced, viz., the conversion hereabove referred to, presents a useful and effective means of combatting hypertension associated with that pressor agent.

~1~9~)3Z

It has been discoverea that the compounds or this invention are possessed of noteworthy activity in inhibiting angiotensin I converting enzyme. Thus, in n vitro techniques desi~ned to evince such activity these compounds are highly effective. For example, they inhibit the pure converting enzyme isolated from rabbit lung tissue at levels from about 0.04 ~m to 0.30 Um. They are, therefore, notable angiotensin I convert-ing enzyme inhibitors.
The compounds o this invention are not limited to _ vitro manifestations of their converting enzyme inhibiting propensity. Upon oral administ~ation, a dose-dependent antihypertensive effect in acute aortic coarctation hypertensive rats is elicited. Oral dosage of from 1 mg/kg to 200 mg/kg admlnistered as a suspension in 0.5~ Methocel solution achieved a reduction of 40-50 mm Hg in mean arterial blood pressure in such rats.
The compounds of this invention can be composed in a variety of dosage forms such as tablets, capsules, solutions and the like for convenient administration employing classical excipients and adjuvants with which there is no in~ompatibility. Such dosage forms contain from 10 to 500 mg of a compound of formuia (I) or a salt thereof in a unit dosage form in accordance with accepted pharmaceutical practice.
In order that this invention may be readily avail-able to and understood by those skilled in the art, the following examples are appended.

* Trademark EX~MPLE I

~-N-(4-Phenylcyclo_ xyl)~lycine~
dimethyleth~l ester Hydrochloride To a stirred solution of 4-phenylcyclohexanone (50.0 g, 0.287 mole) dissolved in methanol (500 ml~ was added a solution of glycine-dimethylethyl ester (12.6 g, 0.096 mole) dissolved in methanol (50 ml) while cooling on an ice bath~ Molecular sieves (10 g, 3 ~) was added, then a solution of NaCNBH3 (18.0 g, 0.287 mole) dissolved in methanol (50 ml) was added dropwise. Stirring was continued overnight at room temperature. The filtered solution was concentrated under reduced pressure to an oily residue. This oily residue was dissolved in ether (500 ml~, washed with NaHCO3, H2O and dried over MgSO4.
The filteEed solution was treated with saturated ether/
HCl (20 ml, ~5 N ether/HCl). The precipitated solid was collected and air dried to give 14.5 g. Recrystalli-zation from acetonitrile and air drying gave 12.2 g.
Melting point, dec. ~250.

Anal. Calcd. for C18H27NO2-HCl: C, 66.34; H, 8.66; N, 4.30 Found: C, 66.32; H~ 8.70; N, 4.20 EXAMPLE II

A) ~an~-N-(3-benzoylthio-1-oxopropyl)-N-(4-~hen~1-cyclohexyl)glycine-~ dimethylethyl ester To a mixture of the compound of Example I (0.60 g, S 0.0018 mole) and CH2C12 (6 ml) was added N-methylmorpho-line (0.44 g, 0.0043 mole~v The resulting mixture was cooled on an ice bath and 3-benzoylthiopropanoyl chloride (0.45 g, 0.0020 mole) was added dropwise. After stirring 10 min the mixtur~ was filtered removing the insolubles.
The CH2C12 solution was washed with 20% citric acid, H2O, 10% NaHCO3, ~O and dried over MgSO4. The filtered solution was concentrated under reduced pressure to dryness and then azeotroped with diethyl ether to a semi-solid residue. This residu~ was dissolved in a small'amount of diethyl ether and precipitated with hexane to give a crystalline solid. Drying in vacuo at 60 overnight gave 0.48 g (0.001 mole, 55%) of trans-N-(3-benzoylthio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine-1,1-dimethylethyl ester.

B) ~a~-!3-Benzoylthio-l-oxoproPYl~-N-(4-~enylc~clo-hexYl) gl~cine P solution of trans-N-(3-benzoylthio-l-oxopropyl)-N-(4-phenylcyclohexyl)glycine~ dimethylethyl ester (0.48 g, 0.001 moles~ and sa~urated acetic acid/llCl (10 ml, saturated at 0) was stirred at room temperature for 30 min. The solution was concentrated under reduced 1199a3~

pressure to an oil~ residue. This residue was chromato-graphed on a column (1.5 x 30 cm) of LH-20 Sephadex eluting with methanol. The fractions containing product were collected and concentrated under reduced pressure to dryness. Hexane was added and the sus?ension concen-trated under reduced pressure to a solid. Drying in vacuo at room temperature gave 200 mg (0.0005 mole 50~) of title compound; melting point 125-128.

Anal. Calcd. for C24H27 4 Found: C, 67.71; H, 6.56; Nr 3.21 EXAMPLE III

A) ~rans-(S)-N-(3-Benzovlthio-2-meth~ -oxopropyl)-N-(4-phenYlcyclohexyl)~lycine-l,l_dimethylethYl ester A solution of the compound of Example I (1.2 g, 0.0037 mole~ was dissolved in C~2Cl2 (20 ml), washed with saturated NaHCO3 (3 x 20 ml), H2O (2 x 20 ml) and dried over MgSO4. The filtered solution was taken to a total volume of 25 ml with CH2Cl2. This solution was cooled on an ice bath (15-20), triethylamine (0.45 g, 0.0044 mole) was added and then (S)-benzoyl-3-mercapto-isobutyric acid chloride [(1.07 g, 0.0044 mole dissolved in C~2C12 (2 ml)] was added dropwise over 2-3 min. The solution was stirred under ambient conditions for 4.0 hours. The resulting solution was washed with saturated NaHCO3 (4 x 30 ml), H2O (2 x 50 ml), 20% citric acid (4 x 30 ml), H2O (2 ~ 50 ml) and dried over MgSO~. The filter2d solution was concentrated under reduced pressure * Trademark 1~9~3~:

to give 1.66 g (0.0033 mole), 89%~ of trans-(S)-N-(3-ben-zoylthio-2-methyl-l-oxopropyl)-N-(4-phenylcyclohexyl)gly-cine-1,1-dimethylethyl ester as an oil.

B) ~ (S)-(-)-N-~3-~enzoylthio-2-methyl-l-oxopro~yl) N~(4-phenylcyclohexyl)qlycine A solutlon of trans-(S)-N-(3-benzoylthio-2-methyl-1-oxopropyl~-N-(4-phenylcyclohexyl)glycine-1,1-dimethylethyl ester (1.60 g, 0.0032 mole) and saturated acetic acid/HC1 (20 ml, saturated at 0) was stirred at room temperature for 1.0` hour. The resulting solution was concentrated under reduced pressure to a semi-solid residue. Tritura-tion with anhydrous ether and air drying gave 1.09 g of a solid. Recrystallization from iso-propanol, air drying and drying in vacuo at 60 gave 0.90 g (0.0020 mole, 62.5~) of title compound; melting point 180-181 ~]20 = -40.6 (C=0.5, MeOH).

Anal. Calcd. for C25H29N04S: C, 68.31; H, 6.65; N, 3.19 Found: C, 68.32; H, 6.58; N, 3.11 EXAMPLE IV

A) ~L~-N-(4-phenylcyclohexyl)glycine~ dimethylethyL
ester H~drochloride To a stirred solution of 4-phenylcyclohexanone (34.26 g, 0.20 mole, Ald.) dissolved in methanol (200 ml) with warming was added dropwise a solution of glycine~ dimetAylethyl ester [~9.17 g, 0.07 mole~

~99Q32 dissolved in methanol (50 ml)l, To this solution was added molecular sieves (5 g, 3 ~)~ This mixture was heated to reflu~ and reflu~ maintained for 6.0 hours.
To the mixture was added more molecular sieve (2 g, 3 ~) and 5% Ed/C dry. This mixture (still warm) was subjected to hydrogenation overnight on a Parr apparatus. The filtered solution was concentrated under reduced pressure to dryness. Hexane (800 ml) was added and a solid was collected. This solid was dissolved in ether and washed with saturated NaHCO3, H2O and dried over MgSO~. The filtered solution was acidified with saturated HCl/ether.
The precipitated solid was collected and air dried to give 8.0 g (0.025 mole) of the cis isomer.

B) c s-(S)-N-(3-Benzovlthio-2-methvl-1-oxo~ro~vl)-N-(4-~henvlcvclohexyl)glvcine-1,1-dirnethvlethvl ester A solution of cis-N-(4-phenylcyclohe~yl)glycine~
dimethylethyl ester hydrochloride [(3.26 g, 0.01 mole) in C~2Cl2 ~7S ml)] was washed with saturated NaHCO3, H2O, dried over MgSO4 and filtered. To this stirred solution was added triethylamine (l.ll g, 0.011 mole) and then (S)-3-benzoyl-~-mercaptoisobuty-ic acid chloride (2.67 g, 0.011 ~oleJ was added dropwise. Stirring was continued for 1.5 hours at room temperature. The solution was washed with 20~ citric acid, H2O, saturated NaHCO3, H2O and dried over L~gSO~. The filtered solution was concentrated under reduced pressure to an oil~
residue (4.8 g). ~his crude oil was chromatographed on Waters "Prep 500" on normal ?hase silica eluting with ethyl acetate/he~ane ~12.5/87.5) giving 4.1 g of ~n oil.
* Trademark 1~903Z

C) cis~(S3 (-~-N-(3-Benzovlthio-2-methyl-l-oxo~ropyl)-N-(4-phenylcyclohexyl)~lycine dicyclohexylamine salt A solution of cis-(S)-N-(3-benzoytthio-2-methyl-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine-1,1-dimethyl-ethyl ester (4.1 q, 0.0085 mole) and saturated acetic acid/HCl (25 mL, saturated at 0) wa~ stirred at room temperature for 1.5 hours. The solution was concen-trated under reduced pressure to an oily residue. This residue was dissolved in CH2Cl2, washed with H2O (2x) and dried over MgSO4. The filtered solution was concen trated under reduced pressure to an oily residue. The oily residue was dissolved in ether and dicyclohexylamine was added. After standiny several days the solid was collected and air dried. Recrystallization from acetoni-trile and air drying gave 3.1 g (0.005 mole, 59%) of title compound. The analytical sample was prepared by drying a small portion ln acuo at room temperature.
Melting point 135-137 [ ]20 = -17.3 (C=0.5, MeOH).

25H29N4S C12H23N: C, 71 57; ~, ~ 44;
Found: C, 71.93; H, 8.04;
N, 4.41 EXAMPLE V

cYclohexyl)glycine Under a layer of nitrogen a mixture of the compound of Example II (B) ~1.0 g, 0.0023 m) and 10 ml H2O was 9~ 2 stirred and cooled in an ice bath. Ammonium hydroxide (10 ml, conc.~ was added and the solution was stirred at room temperature for 18 hr. A precipitate formed and was removed by filtration. The filtrate was extracted with chloroform (7 x 50 ml). The aqueous layer was then cooled and acidified to pH=l with cor.c. HCl. The product precipitated and was collected. It was further purified by silica gel chromatograph~y using CHCl3/MeOH
(18:1) as eluent. Desired fractions from the column were combined and concentrated to an oil which, upon treatment with ether, crystallized yielding 0.069 g (9.3%) of product, m.p. 125-130.

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of N-(4-phenylcyclohexyl)glycines which have the formula (I) (I) in which R represents hydrogen or lower alkyl, and R1 represents hydrogen or benzoyl, which process comprises (a) hydrolysing a 1,1-dimethylethyl ester of a compound of formula (I); or (b) where a compound is desired in which R1 represents hydrogen, subjecting a compound of formula (I) to alkaline hydrolysis; and (c) if desired, converting a compound of formula (I) into a phar-maceutically acceptable salt thereof.

2. A process according to claim 1 wherein the 1,1-dimethylethyl ester of a compound of formula (I) is obtained by reacting N-(4-phenylcyclohexyl) glycine 1,1-dimethylethyl ester with a compound of the formula R1S-CH2-CHR-COX in which R and R1 are as defined in claim 1 and X represents halogen.

3. A process according to claim 2 wherein X is chlorine.

4. A process according to claim 2 wherein the N-(4-phenylcyclohexyl) glycine 1,1-dimethylethyl ester is obtained by reacting 4-phenylcyclohexanone with glycine 1,1-dimethylethyl ester in the presence of NaCNBH3.

5. A process according to claim 1 wherein the hydrolysis is carried out under acidic conditions.

6. N-(4-Phenylcyclohexyl)glycines of the formula (I) as defined in claim 1 whenever prepared by the process of claim 1 or by an obvious equiva-lent thereof.

7. A process for the preparation of trans-(3-benzoylthio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine which comprises subjecting trans-(3-benzoylthio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine 1,1-dimethylethyl ester to hydroly-sis in the presence of acetic and hydrochloric acids.

8. Trans-(3-benzoylthio-1-oxopropyl)-N-[4-phenylcyclohexyl)glycine, whenever prepared by the process of claim 7 or by an obvious equivalent thereof.

9. A process for the preparation of trans-(S)-(-)-N-(3-benzoylthio-2-methyl-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine which comprises hydro-lysing the 1,1-dimethylethyl ester thereof in the presence of acetic and hydrochloric acids.

10. Trans-(S)-(-)-N-(3-benzoylthio-2-methyl-1-oxopropyl)-N-(4-phenyl-cyclohexyl)glycine, whenever prepared by the process of claim 9 or by an obvious equivalent thereof.

11. A process for the preparation of cis-(S)-(-)-N-(3-benzoylthio-2-methyl-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine dicyclohexylamine salt which comprises hydrolysing the corresponding glycine 1,1-dimethylethyl ester in the presence of acetic and hydrochloric acids, and converting the thus obtained product into its dicyclohexylamine salt.

12. Cis-(S)-(-)-N-(3-benzoylthio-2-methyl-1-oxopropyl)-N-(4-phenylcyclo-hexyl)glycine dicyclohexylamine salt whenever prepared by the process of claim 11 or by an obvious equivalent thereof.

13. A process for thc preparation of N-(3-mercapto-1-oxopropyl)-N-(trans-4-phenylcyclohexyl)glycine which comprises subjecting trans-(3-benzoyl-thio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine to hydrolysis in the presence of ammonium hydroxide.

14. N-(3-Mercapto-1-oxopropyl)-N-(trans-4-phenylcyclohexyl)glycine whenever prepared by the process of claim 13 or by an obvious equivalent thereof.